Bioequivalence and Bioavailability Forum

Dear Joshi!

❝ "Confirm if the differences between Tmax for the reference product, and test are statistically significant. If not, this should be made clear in any subsequent report to the RMS. The critical factor here is to convince the assessor that steady state concentrations are of most clinical relevance in a medicinal product for use in a chronic condition (weeks, months or years), rather than a small difference in time to Tmax (hours)"

OK, 'RMS' means 'Reference Member State' - so you are talking about a European Market Authorisation...
To quote from the relevant Guideline:

3.6.1 Statistical analysis
If appropiate to the evaluation the analysis technique for t_max should be non-parametric and should be applied to untransformed data.
3.6.2 Acceptance range for pharmacokinetic parameters
Statistical evaluation of t_max only makes sense if there is a clinically relevant claim for rapid release or action or signs related to adverse effects. The non-parametric 90% confidence interval for this measure of relative bioavailability should lie within a clinically determined range.

The statistical method mentioned by ElMaestro:

Hauschke D, Steinijans VW and E Diletti
A distribution-free procedure for the statistical analysis of bioequivalence studies
Int J Clin Pharm Ther Toxicol 28(2), 72-78 (1990)

What software do you have? Paper and pencil is cumbersome for this procedure. I could help you with StatXac (Cytel), EquivTest/PK (Statistical Solutions), and WinNonlin (Pharsight). SAS is not my thing - PROC STATXACT would do the job there.

❝ This is a Venlafaxine study 150mg Delayed release

Just read Section 3.6.2 over. Is a statistical significant difference clinically relevant? How do C_max of the 150mg DR compare to 75mg IR (safety)? Have also a look at EMEA’s MR guideline.